Atazanavir sulfate is known by the chemical name (3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester sulfate. Atazanavir sulfate is an antiviral agent and HIV protease inhibitor.
Atazanavir sulfate is represented by the structural formula I:

The free base of atazanavir is represented by the structural formula II:

U.S. Pat. No. 5,849,911 describes a series of azapeptide HIV protease inhibitors including atazanavir. According to U.S. Pat. No. 5,849,911, atazanavir is obtained by either crystallization from ethanol/water, or by precipitation with ether from methylene chloride solution of the compound. U.S. Pat. No. 5,849,911 indicates that atazanavir methane sulfonate is precipitated with ether from a methylene chloride solution of atazanavir methane sulfonate, followed by drying under reduced pressure; whereas atazanavir hydrochloride is precipitated by mixing a dioxane solution of atazanavir with a dioxane solution of hydrochloride.
U.S. Pat. No. 6,087,383 describes the preparation of crystalline atazanavir bisulfate in the form of Type-II crystals, which are hydrated, hygroscopic crystalline form, and Type-I crystals, which are anhydrous/desolvated crystalline form. U.S. Pat. No. 6,087,383 discloses the preparation of Type-I crystals by treating atazanavir sulfate with acetonitrile, ethanol-heptane or acetone. Type-II crystals are obtained from isopropanol crystallization.
WO 2005/108349 discloses two crystal forms, Pattern C and Form E3 of atazanavir bisulfate. WO 2005/108349 also discloses a process for the preparation of atazanavir bisulfate Form A. According to WO 2005/108349, Pattern C crystals of atazanavir bisulfate are obtained by stirring a suspension of the Form A crystals of atazanavir bisulfate in water.
Organic Process Research and Development, 6, p. 323-328 (2002) describes the preparation of Type-I crystals of atazanavir sulfate from ethanol crystallization. Organic Process Research and Development, 12, p. 69-75 (2008) discloses crystallization of atazanavir free base with an ethanol-water solvent system.
WO 2010/079497 discloses the crystalline Form H1 of atazanavir sulphate and also a process for the preparation of the same. According to WO 2005/108349, atazanavir sulfate is dissolved in methanol, then ethyl acetate is added, and the solid obtained is collected by filtration and dried to give atazanavir sulfate in crystalline Form H1.
WO 2011/027324 discloses the polymorphic Forms B and P of atazanavir sulfate and processes for their preparation. According to WO 2011/027324, the process for preparing crystalline polymorphic Form B of atazanavir sulfate comprises dissolving atazanavir sulphate in n-butanol and evaporating the solvent at 45-55° C. According to WO 2011/027324, the process for preparing crystalline polymorphic Form P comprises dissolving atazanavir sulfate in n-propanol and evaporating the solvent under vacuum at 35-45° C.
Atazanavir sulphate shows the phenomenon of polymorphism. It is apparent from the prior art that the same solvent can give different polymorphs under different experimental conditions. It has been demonstrated that the known commercial process for preparing crystalline atazanavir sulphate produces, exclusively, a highly crystalline form, Form A, and this is considered as the most suitable polymorph for formulation of atazanavir sulphate. Only very few solvent systems, such as acetone, or acetonitrile, may be used to obtain Form A. However, it is indicated in U.S. Pat. No. '383 and WO '349 that if these solvents are used, the resulting Form A contains impurities, and the most probable impurity is mesityl oxide impurity, which is genotoxic. In order to remove this impurity, atazanavir sulphate must be exposed to repeated washing and drying procedures.
Hence, a person skilled in the art, when synthesizing Form A, would consider the use of solvent systems other than acetone or any other aliphatic ketones, so as to avoid formation of impurities, desirable. However, it has been found that when a solvent medium other than acetone, ethanol/n-heptane system, or acetonitrile is used, Form A is not obtained.
There is a clear need for a process that overcomes the difficulties encountered in the prior art processes for preparing Form A. In particular, there is a need for an alternate process for preparing Form A that can effectively control the generation of potential impurities. The present invention seeks to address these issues.